Deciphering the molecular mechanisms and physiological consequences of macrophage polarisation during Salmonella infection

破译沙门氏菌感染期间巨噬细胞极化的分子机制和生理后果

• 批准号: MR/V031058/1
• 负责人: Teresa Thurston
• 金额: $ 102.99万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV031058%2F1
• 关键词: Deciphering; molecular; mechanisms; physiological; consequences

Macrophages are a key type of immune cell that fights disease-causing microorganisms, such as bacteria. They act by 1) directly fighting the infection by forming a hostile environment to kill the pathogen and 2) producing molecules to alert other immune cells to the danger and ultimately create an inflammatory response. As well as adopting this "killing" state, macrophages can also adopt a "repairing" state, in which they initiate events to reduce inflammation, resolve infection and repair tissues damaged during the inflammatory response. The process by which macrophages adopt either state, known as macrophage polarisation, requires communication within a cell, which is referred to as cell signalling. Proteins are large molecules that carry out critical functions in our cells, from chemical reactions (enzymes) to the regulation of transcription. Transcription makes RNA from the hereditary material (DNA) contained within the cell and can be controlled by proteins called transcription factors. RNA is then the code to make new proteins. Every protein is made up by a unique string of smaller building blocks called amino acids. The sequence of amino acids determines the 3-dimensional structure and function of a protein. During cell signalling, protein modification by small chemical groups can increase, decrease or change their function. During phosphorylation, something called a phosphoryl group is added to specific amino acids of the protein. This reaction is carried out by enzymes called kinases. Some kinases only modify specific types of amino acids called serine and threonine amino acids whereas others can also modify the amino acid tyrosine. Disease-causing bacteria, like Salmonella, use their own proteins to interfere with host cell signalling and thereby host immunity. We have recently found that a protein called SteE, delivered from Salmonella into macrophages, binds a host kinase that normally only modifies serine and threonine amino acids. When together with SteE the kinase now modifies a tyrosine amino acid on a new target, which is a transcription factor. Ultimately, this prompts macrophages to inappropriately adopt the "repair" state rather than the "killing" state. This promotes Salmonella survival and long-term persistence inside the host. This project will 1) define the changes in macrophage DNA transcription mediated by SteE during Salmonella-infection and test whether additional host proteins are required to instruct the "Salmonella-friendly" state of macrophages. 2) Investigate host changes in small molecules (metabolites) during Salmonella infection. 3) Study how the 3D arrangement of SteE and the host kinase are altered in order to allow novel substrates to be modified. Collectively, these findings will reveal the mechanism of how the Salmonella protein SteE promotes disease and provide valuable insight into host immune processes.Salmonella is a major human health challenge; causing a wide range of diseases in humans, from self-limiting diarrhoeal disease, to typhoid fever, a life-threatening systemic disease. Our findings will enable us to gain profound understanding on the pathogenesis of a global, disease-causing bacterium. Ultimately, this may promote the development of novel ways to combat bacterial infections, something which is of vast importance with the rise of antibiotic-resistant bacterial strains.

巨噬细胞是对抗致病微生物（如细菌）的一种关键免疫细胞。它们的作用是：1)通过形成一个敌对的环境来杀死病原体，直接对抗感染；2)产生分子，提醒其他免疫细胞注意危险，最终产生炎症反应。巨噬细胞除了采取这种“杀伤”状态外，还可以采取“修复”状态，在这种状态下，巨噬细胞启动事件来减少炎症，解决感染并修复炎症反应中受损的组织。巨噬细胞采取任何一种状态的过程，被称为巨噬细胞极化，需要细胞内的通信，这被称为细胞信号。蛋白质是大分子，在我们的细胞中执行关键功能，从化学反应（酶）到转录调节。转录从细胞内的遗传物质（DNA）中产生RNA，并可由称为转录因子的蛋白质控制。RNA是制造新蛋白质的密码。每一种蛋白质都是由一串独特的叫做氨基酸的小构件组成的。氨基酸序列决定了蛋白质的三维结构和功能。在细胞信号传递过程中，小的化学基团对蛋白质的修饰可以增加、减少或改变它们的功能。在磷酸化过程中，一种叫做磷酸化基的东西被添加到蛋白质的特定氨基酸上。这个反应是由一种叫做激酶的酶进行的。一些激酶只能修饰特定类型的氨基酸，称为丝氨酸和苏氨酸氨基酸，而其他激酶也可以修饰氨基酸酪氨酸。致病细菌，如沙门氏菌，利用自身的蛋白质干扰宿主细胞信号，从而影响宿主的免疫力。我们最近发现，一种叫做SteE的蛋白质，从沙门氏菌传递到巨噬细胞，与宿主激酶结合，通常只修饰丝氨酸和苏氨酸氨基酸。当与SteE一起时，该激酶现在修饰新靶标上的酪氨酸氨基酸，这是一个转录因子。最终，这促使巨噬细胞不恰当地进入“修复”状态，而不是“杀伤”状态。这促进了沙门氏菌在宿主体内的存活和长期存在。本项目将1)定义沙门氏菌感染期间SteE介导的巨噬细胞DNA转录的变化，并测试是否需要额外的宿主蛋白来指导巨噬细胞的“沙门氏菌友好”状态。2)研究沙门氏菌感染过程中宿主小分子（代谢物）的变化。3)研究如何改变SteE和宿主激酶的三维排列，以便对新的底物进行修饰。总的来说，这些发现将揭示沙门氏菌蛋白SteE如何促进疾病的机制，并为宿主免疫过程提供有价值的见解。沙门氏菌是一项重大的人类健康挑战；在人类中引起广泛的疾病，从自限性腹泻病到危及生命的全身性疾病伤寒。我们的发现将使我们对全球致病细菌的发病机制有更深刻的了解。最终，这可能会促进对抗细菌感染的新方法的发展，随着耐抗生素细菌菌株的兴起，这一点非常重要。

项目成果

Speaking the host language: how Salmonella effector proteins manipulate the host.

说宿主语言：沙门氏菌效应蛋白如何操纵宿主。

• DOI: 10.1099/mic.0.001342
• 发表时间: 2023-06
• 期刊: MICROBIOLOGY-SGM
• 影响因子: 2.8
• 作者: Pillay, Timesh D.;Hettiarachchi, Sahampath U.;Gan, Jiyao;Diaz-Del-Olmo, Ines;Yu, Xiu-Jun;Muench, Janina H.;Thurston, Teresa L. M.;Pearson, Jaclyn S.
• 通讯作者: Pearson, Jaclyn S.

Speaking the host language: how Salmonella effector proteins manipulate the host

说宿主语言：沙门氏菌效应蛋白如何操纵宿主

• DOI: 10.25418/crick.23501289
• 发表时间: 2023
• 作者: Pillay T